Adsorbing material for multiple pathogenic factors of sepsis as well as preparation method and application thereof

Abstract

An adsorbing material for multiple pathogenic factors of sepsis as well as a preparation method and an application thereof are provided. The adsorbing material is formed by coupling a carrier with good mechanical performance and blood compatibility and a ligand with the capacity to adsorb multiple pathogen-associated molecular patterns, and is capable of effectively adsorbing bacterial endotoxin, bacterial genomic DNA, peptidoglycan, lipoteichoic acid, virus RNA, and zymosan from fluids such as blood and the like, and in particular has application value in blood purification for treatment of sepsis.

The invention claimed is: 
     
       1. A preparation method of a ligand of adsorbing materials for adsorbing multiple pathogenic factors of sepsis in fluids, comprising the following steps:
 1) In dichloromethane, compound 1 reacts with di-tert-butyl dicarbonate to generate compound 2, reaction temperature is 20˜30° C., the equivalence ratio of compound 1 and di-tert-butyl dicarbonate is 1:0.5˜2, reaction equation is 
 
       
         
           
           
               
               
           
         
         2) In a saturated solution of ammonia in methanol, compound 3 is generated from compound 2 through hydrogenation under the existence of raney nickel and hydrogen, reaction temperature is 20˜50° C., pressure is 1˜10 Mpa, the mass of raney nickel is 10%˜50% of the mass of compound 2, reaction equation is: 
       
       
         
           
           
               
               
           
         
         3) In ethanol or methanol, compound 3 reacts with α, β-unsaturated nitrile to generate compound 4, reaction temperature is 20˜50° C., the equivalence ratio of compound 3 and α, β-unsaturated nitrile is 1:2˜3, reaction equation is: 
       
       
         
           
           
               
               
           
         
         4) In dichloromethane, compound 5 reacts with N-Hydroxysuccinimide to generate compound 6 under the existence of N,N′-dicyclohexylcarbodiimide and 4-dimethylaminopyridine, reaction temperature is 20˜30° C., the equivalence ratio of compound 5 and N-Hydroxysuccinimide is 1:1˜2, reaction equation is: 
       
       
         
           
           
               
               
           
         
         5) In dioxane, compound 4 reacts with compound 6 to generate compound 7, reaction temperature is 30˜50° C., the equivalence ratio of compound 4 and compound 6 is 1:1˜2, reaction equation is: 
       
       
         
           
           
               
               
           
         
         6) In dioxane, compound 7 reacts with N-Carbobenzoxyoxysuccinimide to generate compound 8, reaction temperature is 30˜50° C., the equivalence ratio of compound 7 and N-Carbobenzoxyoxysuccinimide is 1:1˜2, reaction equation is: 
       
       
         
           
           
               
               
           
         
         7) In ethanol or methanol, compound 8 reacts with di-tert-butyl dicarbonate to generate compound 9 under the existence of raney nickel and hydrogen, reaction temperature is 30˜50° C., the equivalence ratio of compound 8 and di-tert-butyl dicarbonate is 1:0.5˜3, pressure is 1˜10 Mpa, the mass of the raney nickel is 10%˜50% of the mass of compound 8, reaction equation is: 
       
       
         
           
           
               
               
           
         
         8) In methanol, compound 10 is generated from compound 9 under the existence of Palladium on carbon and hydrogen, reaction temperature is 20˜50° C., pressure ranges from atmospheric pressure to 10 MPa, the mass of the Palladium on carbon is 10%˜30% of the mass of compound 9, reaction equation is: 
       
       
         
           
           
               
               
           
         
         9) In dichloromethane, compound 10 reacts with succinic anhydride to generate compound 11 under the existence of 4-dimethylaminopyridine, reaction temperature is 20˜30° C., the equivalence ratio of compound 10 and succinic anhydride is 1:1˜2, reaction equation is: 
       
       
         
           
           
               
               
           
         
         10) In ethyl acetate, compound 11 reacts with N-Hydroxysuccinimide to generate compound 12, reaction temperature is 20˜30° C., the equivalence ratio of compound 11 and N-Hydroxysuccinimide is 1:1˜2, reaction equation is: 
       
       
         
           
           
               
               
           
         
         wherein n 1 -n 4  is an integer between 1-6, and n 5  is an integer between 0-3. 
       
     
     
       2. The method according to  claim 1 , wherein the multiple pathogenic factors of sepsis include bacterial endotoxin, bacterial genomic DNA, peptidoglycan, lipoteichoic acid, virus RNA and/or zymosan. 
     
     
       3. The method according to  claim 1 , wherein the fluids include human blood or blood plasma or drug injection or liquid biological reagent. 
     
     
       4. An adsorbing material for multiple pathogenic factors of sepsis, wherein the material is formed by coupling the ligand prepared through the method of  claim 1  and a carrier, whose molecular structure is shown as follows 
       
         
           
           
               
               
           
         
       
     
     
       5. The adsorbing material according to  claim 4 , wherein the carrier is amino-functionalized agarose or amino-functionalized polystyrene resin. 
     
     
       6. A preparation method of an adsorbing material for adsorbing multiple pathogenic factors of sepsis, comprising following steps:
 1) In tetrahydrofuran or tetrahydrofuran aqueous solution or ethanol aqueous solution, compound 12 reacts with carrier M to generate compound 13, the mass ratio of compound 12 and carrier M is 0.01˜1:100, reaction equation is: 
 
       
         
           
           
               
               
           
         
         2) Blockade of residual amino of carrier: 
         In N,N-Diisoprolethylaamine, acetic anhydride is added into compound 13, and reacts with compound 13 to obtain crude product in which the residual amino of carrier are blocked, the equivalence ratio of compound 13 and acetic anhydride is 1:1˜2, reaction equation is: 
       
       
         
           
           
               
               
           
         
         3) Preparation of end product: 
         In methanol, 2˜6M hydrochloric acid in methanol is added into the crude product in ice bath, the reaction generates the end product MTAM, the volume ratio of the crude product to hydrochloric acid in methanol is 1:0.5˜1.5, reaction equation is: 
       
       
         
           
           
               
               
           
         
         wherein n 1 -n 4  is an integer between 1-6, and n 5  is an integer between 0-3. 
       
     
     
       7. A blood purification device for treatment of sepsis comprising the adsorbing material according to  claim 4 . 
     
     
       8. A blood purification device for treatment of sepsis comprising the adsorbing material according to  claim 5 .